The Future: Stem Cells and Biological Approaches for Pulp Regeneration

  • Jacques E. NörEmail author
  • Carolina Cucco


Achieving long-lasting and complete pulp regeneration in teeth with deep caries or severe trauma remains a significant clinical challenge. In teeth with immature apices and exposed vital pulp tissue, partial or complete pulpotomy is typically indicated to preserve pulp function and allow for continued root development. In cases where injury caused loss of pulp vitality and arrested root development, teeth may remain with poor crown-to-root ratio, a root with very thin walls, and an open apex. The ideal treatment in such cases would be to regenerate a functional dentin–pulp complex that would enable the completion of root development and thickening of dentinal walls. Emerging evidence suggests that this can be achieved with the recruitment of apical stem cells toward the root canal and/or the transplantation of stem cells using a tissue engineering-based approach. In this chapter, we will discuss the evidence that provides the rationale for regenerative approaches for the treatment of pulp injury or pulp necrosis.


Root Canal Dental Pulp Pulp Tissue Dental Pulp Cell Dental Pulp Stem Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Petersen PE. World Health Organization global policy for improvement of oral health – World Health Assembly 2007. Int Dent J. 2008;58(3):115–21.CrossRefPubMedGoogle Scholar
  2. 2.
    Casagrande L, Cordeiro MM, Nör SA, Nör JE. Dental pulp stem cells in regenerative dentistry. Odontology. 2011;99(1):1–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Nör JE. Tooth regeneration in operative dentistry. Oper Dent. 2006;31(6):633–42.CrossRefPubMedGoogle Scholar
  4. 4.
    Nakashima M, Reddi AH. The application of bone morphogenetic proteins to dental tissue engineering. Nat Biotechnol. 2003;21(9):1025–32.CrossRefPubMedGoogle Scholar
  5. 5.
    Thesleff I. Epithelial-mesenchymal signaling regulating tooth morphogenesis. J Cell Sci. 2003;116(Pt 9):1647–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Pispa J, Thesleff I. Mechanisms of ectodermal organogenesis. Dev Biol. 2003;262(2):195–205.CrossRefPubMedGoogle Scholar
  7. 7.
    Thesleff I, Mikkola M. The role of growth factors in tooth development. Int Rev Cytol. 2002;217:93–135.CrossRefPubMedGoogle Scholar
  8. 8.
    Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000;97(25):13625–30.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Miura M, Gronthos S, Zhao M, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A. 2003;100(10):5807–12.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Gronthos S, Brahim J, Li W, et al. Stem cell properties of human dental pulp stem cells. J Dent Res. 2002;81(8):531–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Paino F, Ricci G, De Rosa A, et al. Ecto-mesenchymal stem cells from dental pulp are commit-ted to differentiate into active melanocytes. Eur Cell Mater. 2010;20:295–305.PubMedGoogle Scholar
  12. 12.
    Shi S, Robey PG, Gronthos S. Comparison of human dental pulp and bone marrow stromal stem cells by cDNA microarray analysis. Bone. 2001;29:532–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Seo BM, Miura M, Gronthos S, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet. 2004;364(9429):149–55.CrossRefPubMedGoogle Scholar
  14. 14.
    Wei X, Ling J, Wu L, Liu L, Xiao Y. Expression of mineralization markers in dental pulp cells. J Endod. 2007;33(6):703–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Gay IC, Chen S, MacDougall M. Isolation and characterization of multipotent human periodontal ligament stem cells. Orthod Craniofac Res. 2007;10(3):149–60.CrossRefPubMedGoogle Scholar
  16. 16.
    Cordeiro MM, Dong Z, Kaneko T, et al. Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth. J Endod. 2008;34(8):962–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Sakai VT, Zhang Z, Dong Z, et al. SHED differentiate into functional odontoblasts and endothelium. J Dent Res. 2010;89(8):791–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Demarco FF, Casagrande L, Zhang Z, Dong Z, Tarquino SB, Zeitlin BD, Shi S, Smith AJ, Nör JE. Effects of morphogen and scaffold porogen on the differentiation of dental pulp stem cells. J Endod. 2010;36(11):1805–11.CrossRefPubMedGoogle Scholar
  19. 19.
    Sonoyama W, Liu Y, Yamaza T, et al. Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: a pilot study. J Endod. 2008;34(2):166–71.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Huang GT, Sonoyama W, Liu Y, Liu H, Wang S, Shi S. The hidden treasure in apical papilla: the potential role in pulp/dentin regeneration and bioroot engineering. J Endod. 2008;34:645–51.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Iohara K, Nakashima M, Ito M, Ishikawa M, Nakasima A, Akamine A. Dentin regeneration by dental pulp stem cell therapy with recombinant human bone morphogenetic protein 2. J Dent Res. 2004;83(8):590–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Machado CV, Passos ST, Campos TM, Bernardi L, Vilas-Bôas DS, Nör JE, Telles PD, Nasci-mento IL. The dental pulp stem cell niche based on aldehyde dehydrogenase 1 expression. Int End J. 2015. doi: 10.1111/iej.12511. [Epub ahead of print].
  23. 23.
    Smith AJ, Matthews JB, Hall RC. Transforming growth-factor-b1 (TGF-b1) in dentin matrix. Ligand activation and receptor expression. Eur J Oral Sci. 1998;106 Suppl 1:179–84.CrossRefPubMedGoogle Scholar
  24. 24.
    Roberts-Clark DJ, Smith AJ. Angiogenic growth factors in human dentine matrix. Arch Oral Biol. 2000;45(11):1013–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Smith AJ, Cassidy N, Perry H, Begue-Kirn C, Ruch JV, Lesot H. Reactionary dentinogenesis. Int J Dev Biol. 1995;39:273–80.PubMedGoogle Scholar
  26. 26.
    Graham L, Cooper PR, Cassidy N, Nör EJ, Sloan AJ, Smith AJ. The effect of calcium hydroxide on solubilization of bio-active dentine matrix components. Biomaterials. 2006;27(14):2865–73.CrossRefPubMedGoogle Scholar
  27. 27.
    Murray PE, Smith AJ. Saving pulps – a biological basis. An overview. Prim Dent Care. 2002;9(1):21–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Tziafas D. Basic mechanisms of cytodifferentiation and dentinogenesis during dental pulp repair. Int J Dev Biol. 1995;39:281–90.PubMedGoogle Scholar
  29. 29.
    Tziafas D, Alvanou A, Panagiotakopoulos N. Induction of odontoblast-like cell differentiation in dog dental pulps after in vivo implantation of dentine matrix components. Arch Oral Biol. 1995;40(10):883–93.CrossRefPubMedGoogle Scholar
  30. 30.
    Smith AJ, Murray PE, Sloan AJ, Matthews JB, Zhao S. Trans-dentinal stimulation of tertiary dentinogenesis. Adv Dent Res. 2001;15:51–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Nakashima M, Nagasawa H, Yamada Y, Reddi AH. Regulatory role of transforming growth factor-b, bone morphogenetic protein-2, and protein-4 on gene expression of extracellular matrix proteins and differentiation of dental pulp cells. Dev Biol. 1994;162(1):18–28.CrossRefPubMedGoogle Scholar
  32. 32.
    Iohara K, Zheng L, Ito M, Tomokiyo A, Matsushita K, Nakashima M. Side population cells isolated from porcine dental pulp tissue with self-renewal and multipotency for dentinogenesis, chondrogenesis, adipogenesis, and neurogenesis. Stem Cells. 2006;24(11):2493–503.CrossRefPubMedGoogle Scholar
  33. 33.
    Sloan AJ, Smith AJ. Stimulation of the dentine–pulp complex of rat incisor teeth by trans-forming growth factor-b isoforms 1–3 in vitro. Arch Oral Biol. 1999;44(2):149–56.CrossRefPubMedGoogle Scholar
  34. 34.
    Sloan AJ, Rutherford RB, Smith AJ. Stimulation of the rat dentine–pulp complex by bone morphogenetic protein-7 in vitro. Arch Oral Biol. 2000;45(2):173–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Six N, Decup F, Lasfargues JJ, Salih E, Goldberg M. Osteogenic proteins (bone sialoprotein and bone morphogenetic protein-7) and dental pulp mineralization. J Mater Sci Mater Med. 2002;13(2):225–32.CrossRefPubMedGoogle Scholar
  36. 36.
    Lovschall H, Fejerskov O, Flyvberg A. 63 pulp-capping with recombinant human insulin-like growth factor I (rhIGF-I) in rat molars. Adv Dent Res. 2001;15:108–12.CrossRefPubMedGoogle Scholar
  37. 37.
    Almushayt A, Narayanan K, Zaki AE, George A. Dentin matrix protein 1 induces cytodifferentiation of dental pulp stem cells into odontoblasts. Gene Ther. 2006;13(7):611–20.CrossRefPubMedGoogle Scholar
  38. 38.
    Alliot-Licht B, Bluteau G, Magne D, et al. Dexamethasone stimulates differentiation of odontoblast-like cells in human dental pulp cultures. Cell Tissue Res. 2005;321(3):391–400.CrossRefPubMedGoogle Scholar
  39. 39.
    Couble ML, Farges JC, Bleicher F, Perrat Mabillon B, Boudeulle M, Magloire H. Odontoblast differentiation of human dental pulp cells in explant cultures. Calcif Tissue Int. 2000;66(2):129–38.CrossRefPubMedGoogle Scholar
  40. 40.
    Gomes A, Azevedo H, Malafaya P, et al. Tissue engineering, van Blitterswijk C, editor. Burlington/San Diego: Elsevier; 2008.Google Scholar
  41. 41.
    Chan G, Mooney DJ. New materials for tissue engineering: towards greater control over the biological response. Trends Biotechnol. 2008;26(7):382–92.CrossRefPubMedGoogle Scholar
  42. 42.
    Langer R, Tirrell DA. Designing materials for biology and medicine. Nature. 2004;428(6982):487–92.CrossRefPubMedGoogle Scholar
  43. 43.
    Langer R, Vacanti JP. Tissue engineering. Science. 1993;260(5110):920–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Curtis M, Riehle M. Tissue engineering: the biophysical background. Phys Med Biol. 2001;46(4):47–65.CrossRefGoogle Scholar
  45. 45.
    Torneck CD, Smith J. Biologic effects of endodontic procedures on developing incisor teeth. I. Effect of partial and total pulp removal. Oral Surg Oral Med Oral Pathol. 1970;30:258–66.CrossRefPubMedGoogle Scholar
  46. 46.
    Torneck CD, Smith JS, Grindall P. Biologic effects of endodontic procedures on developing incisor teeth. II. Effect of pulp injury and oral contamination. Oral Surg Oral Med Oral Pathol. 1973;35:378–88.CrossRefPubMedGoogle Scholar
  47. 47.
    Torneck CD, Smith JS, Grindall P. Biologic effects of endodontic procedures on developing incisor teeth. 3. Effect of debridement and disinfection procedures in the treatment of experimentally induced pulp and periapical disease. Oral Surg Oral Med Oral Pathol. 1973;35:532–40.CrossRefPubMedGoogle Scholar
  48. 48.
    Cvek M. Prognosis of luxated non-vital maxillary incisors treated with calcium hydroxide and filled with gutta-percha. A retrospective clinical study. Endod Dent Traumatol. 1992;8:45–55.CrossRefPubMedGoogle Scholar
  49. 49.
    Frank AL. Therapy for the divergent pulpless tooth by continued apical formation. J Am Dent Assoc. 1966;72:87–93.CrossRefPubMedGoogle Scholar
  50. 50.
    Torabinejad M, Chivian N. Clinical applications of mineral trioxide aggregate. J Endod. 1999;25:197–205.CrossRefPubMedGoogle Scholar
  51. 51.
    Kleier CJ, Barr ES. A study of endodontically apexified teeth. Endod Dent Traumatol. 1991;7:112–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Mohammadi Z, Dummer PM. Properties and applications of calcium hydroxide in endodontics and dental traumatology. Int Endod J. 2011;44:697–730.CrossRefPubMedGoogle Scholar
  53. 53.
    Mooney DJ, Powell C, Piana J, Rutherford B. Engineering dental pulp-like tissue in vitro. Biotechnol Prog. 1996;12(6):865–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Bohl KS, Shon J, Rutherford B, Mooney DJ. Role of synthetic extracellular matrix in development of engineered dental pulp. J Biomater Sci Polym. 1998;9(7):749–64.CrossRefGoogle Scholar
  55. 55.
    Prescott RS, Alsanea R, Fayad MI, et al. In vivo generation of dental pulp-like tissue by using dental pulp stem cells, a collagen scaffold, and dentin matrix protein 1 after subcutaneous transplantation in mice. J Endod. 2008;34(4):421–6.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Galler KM, Aulisa L, Regan KR, D’Souza RN, Hartgerink JD. Self-assembling multidomain peptide hydrogels: designed susceptibility to enzymatic cleavage allows enhanced cell migration and spreading. J Am Chem Soc. 2010;132(9):3217–23.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Galler KM, Cavender A, Yuwono V, et al. Self-assembling peptide amphiphile nanofibers as a scaffold for dental stem cells. Tissue Eng Part A. 2008;14(12):2051–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Ötsby BN. The role of the blood clot in endodontic therapy. An experimental histologic study. Acta Odontol Scand. 1961;19:324–53.Google Scholar
  59. 59.
    Torabinejad M, Turman M. Revitalization of tooth with necrotic pulp and open apex by using platelet-rich plasma: a case report. J Endod. 2011;37:265–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Whitherspoon DE, Small JC, Regan JD, Nunn M. Retrospective analysis of open apex teeth obturated with mineral trioxide aggregate. J Endod. 2008;34:1171–6.CrossRefGoogle Scholar
  61. 61.
    Hargreaves KM, Giesler T, Henry M, Wang Y. Regeneration potential of the young permanent tooth: what does the future hold? J Endod. 2008;37(7 suppl):S51–6.CrossRefGoogle Scholar
  62. 62.
    Sato I, Ando-Kurihara N, Kota K, Iwaku M, Hoshino E. Sterilization of infected root-canal dentine by topical application of a mixture of ciprofloxacin, metronidazole and minocycline in situ. Int Endod J. 1996;29:118–24.CrossRefPubMedGoogle Scholar
  63. 63.
    Hoshino E, Kurihara-Ando N, Sato I, et al. In-vitro antibacterial susceptibility of bacteria taken from infected root dentine to a mixture of ciprofloxacin, metronidazole and minocycline. Int Endod J. 1996;29:125–30.CrossRefPubMedGoogle Scholar
  64. 64.
    Kindler V. Postnatal stem cell survival: does the niche, a rare harbor where to resist the ebb tide of differentiation, also provide lineage-specific instructions? J Leukoc Biol. 2005;78:836–44.CrossRefPubMedGoogle Scholar
  65. 65.
    Trojani C, Weiss P, Michiels JF, et al. Three-dimensional culture and differentiation of human osteogenic cells in an injectable hydroxypropyl-methylcellulose hydrogel. Biomaterials. 2005;26:5509–17.CrossRefPubMedGoogle Scholar
  66. 66.
    Alhadlaq A, Mao JJ. Tissue-engineered osteochondral constructs in the shape of an articular condyle. J Bone Joint Surg Am. 2005;87:936–44.CrossRefPubMedGoogle Scholar
  67. 67.
    Luo Y, Shoichet MS. A photolabile hydrogel for guided three-dimensional cell growth and migration. Nat Mater. 2004;3:249–53.CrossRefPubMedGoogle Scholar
  68. 68.
    Galler KM, Cavender AC, Koeklue U, Suggs LJ, Schmalz G, D’Souza RN. Bioengineering of dental stem cells in PEGylated fibrin gel. Regen Med. 2011;6(2):191–200.CrossRefPubMedGoogle Scholar
  69. 69.
    Rosa V, Zhang Z, Grande RH, Nör JE. Dental pulp tissue engineering in full length human root canals. J Dent Res. 2013;92(11):970–5.PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Venugopal J, Ramakrishna S. Applications of polymer nanofibers in biomedicine and bio-technology. Appl Biochem Biotechnol. 2005;125:147–58.CrossRefPubMedGoogle Scholar
  71. 71.
    Peter SJ, Miller MJ, Yasko AW, Yaszemski MJ, Mikos AG. Polymer concepts in tissue engineering. J Biomed Mater Res. 1998;43:422–7.CrossRefPubMedGoogle Scholar
  72. 72.
    Syed-Picard FN, Ray Jr HL, Kumta PN, Sfeir C. Scaffoldless tissue-engineered dental pulp cell constructs for endodontic therapy. J Dent Res. 2014;93(3):250–5.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Cariology, Restorative Sciences, EndodonticsUniversity of Michigan School of DentistryAnn ArborUSA
  2. 2.Department of Cariology, Restorative Sciences, EndodonticsUniversity of Michigan School of DentistryAnn ArborUSA

Personalised recommendations